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CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues.

ABSTRACT: The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2-overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach.

SUBMITTER: Tat J

PROVIDER: S-EPMC5777741 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues.

Tat John J Loriot Céline C Henze Martha M Spruck Charles C Felding Brunhilde H BH Reed Steven I SI

Oncotarget 20171204 70

The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhan ...[more]

PMID: 29383129

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Project description:BackgroundTumor protein 63 (p63) is a transcription factor of the p53 gene family involved in differentiation of several tissues including squamous epithelium. p63 immunohistochemistry is broadly used for tumor classification but published data on its expression in cancer is conflicting.MethodsTo comprehensively catalogue p63 expression, tissue microarrays (TMAs) containing 12,620 tissue samples from 115 tumor entities and 76 normal tissue types were analyzed.Resultsp63 expression was seen in various normal tissues including squamous epithelium and urothelium. At least occasional weak p63 positivity could be detected in 61 (53%) of 115 different tumor types. The frequencies of p63 positivity was highest in squamous cell carcinomas irrespective of their origin (96-100%), thymic tumors (100%), urothelial carcinomas (81-100%), basal type tumors such as basal cell carcinomas (100%), and various salivary gland neoplasias (81-100%). As a rule, p63 was mostly expressed in cancers derived from p63 positive normal tissues and mostly not detectable in tumors derived from p63 negative cancers. However, exceptions from this rule occurred. A positive p63 immunostaining in cancers derived from p63 negative tissues was unrelated to aggressive phenotype in 422 pancreatic cancers, 160 endometrium cancers and 374 ovarian cancers and might be caused by aberrant squamous differentiation or represent stem cell properties. In 355 gastric cancers, aberrant p63 expression occurred in 4% and was linked to lymph node metastasis (p = 0.0208). Loss of p63 in urothelial carcinomas - derived from p63 positive urothelium - was significantly linked to advanced stage, high grade (p < 0.0001 each) and poor survival (p < 0.0001) and might reflect clinically relevant tumor dedifferentiation.ConclusionThe high prevalence of p63 expression in specific tumor types makes p63 immunohistochemistry a suitable diagnostic tool. Loss of p63 expression might constitute a feature of aggressive cancers.

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CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues.

Publications

CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues.

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